Project Summary/Abstract Drug and alcohol use and addiction are heritable phenotypes that are leading causes of morbidity and mortality worldwide. Hundreds of loci have now been strongly linked to risk for substance use and addiction, and many more genes remain to be discovered. Studies of impactful rare genetic variants are accelerating our understanding of genetic influences of complex disease and producing compelling targets for intervention research and drug development. The current proposal provides a framework by which rare variants can be efficiently identified and evaluated in humans for their effects on addiction using large and readily available datasets. Such datasets often have sparse phenotyping, especially for behavioral and psychiatric phenotypes. Our proposed framework overcomes this challenge through re-contact and reassessment of rare variant carriers and their family members, allowing measurement of psychiatric phenotypes far beyond that available in biobanks. We take full advantage of a multidisciplinary team, advanced genomic technology, diverse analytical approaches, and detailed deep phenotypic assessment on a sample of large extended families. We will use large highly-powered GWAS and whole genome sequencing datasets to identify rare putatively deleterious variants within substance-use-associated loci. Upon functional validation of the rare deleterious variant in cell lines, we will use a novel procedure to impute such variants into the Michigan Genomics Initiative Biobank, thereby identifying carriers of rare deleterious alleles. These individuals, and their families, will be re-contacted and receive standard and tailored assessments of their substance use/dependence history, psychiatric, neurocognitive, and psychosocial function. The proposed framework offers a new approach to investigate the human biology underlying GWAS hits, identifying therapeutic targets and improving our understanding of the etiology of addiction.